Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see Precautions).
Treatment: Adults: Therapy must be initiated with the specified loading dose regimen of either intravenous or oral voriconazole to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of the high oral bioavailability (96%; see Pharmacology: Pharmacokinetics under Actions), switching between intravenous and oral administration is appropriate when clinically indicated.
Detailed information on dosage recommendations is provided on the following table: See Table 3.
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Duration of treatment: Treatment duration should be as short as possible depending on the patient's clinical and mycological response. Long term exposure to voriconazole greater than 180 days (6 months) requires careful assessment of the benefit-risk balance (see Pharmacology: Pharmacodynamics under Actions).
Dosage adjustment (Adults): If patient response to treatment is inadequate, the maintenance dose may be increased to 300 mg twice daily for oral administration. For patients less than 40 kg the oral dose may be increased to 150 mg twice daily.
If patient is unable to tolerate treatment at a higher dose, reduce the oral dose by 50 mg steps to the 200 mg twice daily (or 100 mg twice daily for patients less than 40 kg) maintenance dose.
In case of use as prophylaxis, refer to table 4 below.
Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg): Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole more similarly to children than to adults.
The recommended dosing regimen is as follows: See Table 4.
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It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
These oral dose recommendations for children are based on studies in which voriconazole was administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastroenteric transit time In paediatric patients, the absorption of tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2 to <12.
All other adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight) Voriconazole should be dosed as adults.
Dosage adjustment (Children [2 to <12 years] and young adolescents with low body weight [12 to 14 years and <50 kg]): If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patient is unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).
Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see Adverse Effects and Pharmacology: Pharmacokinetics under Actions).
Prophylaxis in Adults and Children: Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days.
Prophylaxis should be as short as possible depending on the risk for developing invasive fungal infection (IFI) as defined by neutropenla or immunosuppression. It may only be continued up to 180 days after transplantation in case of continuing immunosuppression or graft versus host disease (GvHD) (see Pharmacology: Pharmacodynamics under Actions).
Dosage: The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups. Please refer to the treatment tables above.
Duration of prophylaxis: The safety and efficacy of voriconazole use for longer than 180 days has not been adequately studied in clinical trials.
Use of voriconazole in prophylaxis for greater than 180 days (6 months) requires careful assessment of the benefit-risk balance (see Precautions and Pharmacology: Pharmacokinetics under Actions).
The following instructions apply to both Treatment and Prophylaxis: Dosage adjustment: For prophylaxis, dose adjustments are not recommended in the case of lack of efficacy or treatment-related adverse events. In the case of treatment-related adverse events, discontinuation of voriconazole and use of alternative antifungal agents must be considered (see Precautions and Adverse Reactions).
Dosage adjustments in case of co-administration: Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see Precautions and Interactions.
The combination of voriconazole with rifabutin should, if possible be avoided. However, if the combination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see Precautions and Interactions.
Efavirenz may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, ie, to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see Precautions and Interactions).
Elderly patients: No dose adjustment is necessary for elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Patients with renal impairment: The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Voriconazole is haemodialysed with a clearance of 121 ml/min.
A 4-hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
Patients with hepatic impairment: It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving voriconazole (see Pharmacology: Pharmacokinetics under Actions).
Voriconazole has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).
There is limited data on the safety of voriconazole in patients with abnormal liver function tests (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], or total bilirubin >5 times the upper limit of normal).
Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with severe hepatic impairment must be carefully monitored for drug toxicity (see Adverse Reactions).
Paediatric population: The safety and efficacy of voriconazole in children below 2 years has not been established.
Currently available data are described in Adverse Reactions and Pharmacology: Pharmacodynamics under Actions but no recommendation on a posology can be made.
Method of administration: Voriconazole tablets are to be taken at least one hour before, or one hour following, a meal.